Clinical question: Is functional status in the elderly maintained over time after initiating long-term dialysis?

Background: Quality-of-life maintenance often is used as a goal when initiating long-term dialysis in elderly patients with end-stage renal disease. More elderly patients are being offered long-term dialysis treatment. Little is known about the functional status of elderly patients on long-term dialysis.

Study design: Retrospective cohort study.

Setting: U.S. nursing homes.

Synopsis: By cross-linking data from two population-based administrative datasets, this study identified 3,702 nursing home patients (mean 73.4 years) who had started long-term dialysis and whose functional status had been assessed. Activities of daily living assessments before and at three-month intervals after dialysis initiation were compared to see if functional status was maintained.

Within three months of starting dialysis, 61% of patients had a decline in functional status or had died. By one year, only 1 in 8 patients had maintained their pre-dialysis functional status.

Decline in functional status cannot be attributed solely to dialysis because study patients were not compared to patients with chronic kidney disease who were not dialyzed. In addition, these results might not apply to all elderly patients on dialysis, as the functional status of elderly nursing home patients might differ significantly from those living at home.

Bottom line: Functional status is not maintained in most elderly nursing home patients in the first 12 months after long-term dialysis is initiated. Elderly patients considering dialysis treatment should be aware that dialysis might not help maintain functional status and quality of life.

Citation: Kurella Tamura MK, Covinsky KE, Chertow GM, Yaffe C, Landefeld CS, McCulloch CE. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med. 2009;361(16):1539-1547.

Clinical question: Is functional status in the elderly maintained over time after initiating long-term dialysis?

Background: Quality-of-life maintenance often is used as a goal when initiating long-term dialysis in elderly patients with end-stage renal disease. More elderly patients are being offered long-term dialysis treatment. Little is known about the functional status of elderly patients on long-term dialysis.

Study design: Retrospective cohort study.

Setting: U.S. nursing homes.

Synopsis: By cross-linking data from two population-based administrative datasets, this study identified 3,702 nursing home patients (mean 73.4 years) who had started long-term dialysis and whose functional status had been assessed. Activities of daily living assessments before and at three-month intervals after dialysis initiation were compared to see if functional status was maintained.

Within three months of starting dialysis, 61% of patients had a decline in functional status or had died. By one year, only 1 in 8 patients had maintained their pre-dialysis functional status.

Decline in functional status cannot be attributed solely to dialysis because study patients were not compared to patients with chronic kidney disease who were not dialyzed. In addition, these results might not apply to all elderly patients on dialysis, as the functional status of elderly nursing home patients might differ significantly from those living at home.

Bottom line: Functional status is not maintained in most elderly nursing home patients in the first 12 months after long-term dialysis is initiated. Elderly patients considering dialysis treatment should be aware that dialysis might not help maintain functional status and quality of life.

Citation: Kurella Tamura MK, Covinsky KE, Chertow GM, Yaffe C, Landefeld CS, McCulloch CE. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med. 2009;361(16):1539-1547.

Clinical question: Is functional status in the elderly maintained over time after initiating long-term dialysis?

Background: Quality-of-life maintenance often is used as a goal when initiating long-term dialysis in elderly patients with end-stage renal disease. More elderly patients are being offered long-term dialysis treatment. Little is known about the functional status of elderly patients on long-term dialysis.

Study design: Retrospective cohort study.

Setting: U.S. nursing homes.

Synopsis: By cross-linking data from two population-based administrative datasets, this study identified 3,702 nursing home patients (mean 73.4 years) who had started long-term dialysis and whose functional status had been assessed. Activities of daily living assessments before and at three-month intervals after dialysis initiation were compared to see if functional status was maintained.

Within three months of starting dialysis, 61% of patients had a decline in functional status or had died. By one year, only 1 in 8 patients had maintained their pre-dialysis functional status.

Decline in functional status cannot be attributed solely to dialysis because study patients were not compared to patients with chronic kidney disease who were not dialyzed. In addition, these results might not apply to all elderly patients on dialysis, as the functional status of elderly nursing home patients might differ significantly from those living at home.

Bottom line: Functional status is not maintained in most elderly nursing home patients in the first 12 months after long-term dialysis is initiated. Elderly patients considering dialysis treatment should be aware that dialysis might not help maintain functional status and quality of life.

Citation: Kurella Tamura MK, Covinsky KE, Chertow GM, Yaffe C, Landefeld CS, McCulloch CE. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med. 2009;361(16):1539-1547.

Clinical question: Does long-term inhaled corticosteroid therapy, with and without long-acting beta-agonists, decrease airway inflammation and improve lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD)?

Background: Guideline-recommended treatment of COPD with inhaled corticosteroids and long-acting beta-agonists improves symptoms and exacerbation rates; little is known about the impact of these therapies on inflammation and long-term lung function.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Two university medical centers in the Netherlands.

Synopsis: One hundred one steroid-naïve patients, ages 45 to 75 who were current or former smokers with moderate to severe COPD, were randomized to one of four regimens: 1) fluticasone for six months, then placebo for 24 months; 2) fluticasone for 30 months; 3) fluticasone and salmeterol for 30 months; or 4) placebo for 30 months. The primary outcome was inflammatory cell counts in bronchial biopsies/induced sputum. Secondary outcomes included postbronchodilator spirometry, methacholine hyperresponsiveness, and self-reported symptoms and health status. Patients with asthma were excluded.

Short-term fluticasone therapy decreased inflammation and improved forced expiratory volume in one second (FEV1). Long-term therapy also decreased the rate of FEV1 decline, reduced dyspnea, and improved health status. Discontinuation of therapy at six months led to inflammation relapse with worsened symptoms and increased rate of FEV1 decline. The addition of long-acting beta-agonists did not provide additional anti-inflammatory benefits, but it did improve FEV1 and dyspnea at six months.

Additional studies are needed to further define clinical outcomes and assess the cost benefit of these therapies.

Bottom line: Inhaled corticosteroids decrease inflammation in steroid-naïve patients with moderate to severe COPD and might decrease the rate of lung function decline. Long-acting beta-agonists do not offer additional anti-inflammatory benefit.

Citation: Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;151(8):517-527.

Clinical question: Does long-term inhaled corticosteroid therapy, with and without long-acting beta-agonists, decrease airway inflammation and improve lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD)?

Background: Guideline-recommended treatment of COPD with inhaled corticosteroids and long-acting beta-agonists improves symptoms and exacerbation rates; little is known about the impact of these therapies on inflammation and long-term lung function.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Two university medical centers in the Netherlands.

Synopsis: One hundred one steroid-naïve patients, ages 45 to 75 who were current or former smokers with moderate to severe COPD, were randomized to one of four regimens: 1) fluticasone for six months, then placebo for 24 months; 2) fluticasone for 30 months; 3) fluticasone and salmeterol for 30 months; or 4) placebo for 30 months. The primary outcome was inflammatory cell counts in bronchial biopsies/induced sputum. Secondary outcomes included postbronchodilator spirometry, methacholine hyperresponsiveness, and self-reported symptoms and health status. Patients with asthma were excluded.

Short-term fluticasone therapy decreased inflammation and improved forced expiratory volume in one second (FEV1). Long-term therapy also decreased the rate of FEV1 decline, reduced dyspnea, and improved health status. Discontinuation of therapy at six months led to inflammation relapse with worsened symptoms and increased rate of FEV1 decline. The addition of long-acting beta-agonists did not provide additional anti-inflammatory benefits, but it did improve FEV1 and dyspnea at six months.

Additional studies are needed to further define clinical outcomes and assess the cost benefit of these therapies.

Bottom line: Inhaled corticosteroids decrease inflammation in steroid-naïve patients with moderate to severe COPD and might decrease the rate of lung function decline. Long-acting beta-agonists do not offer additional anti-inflammatory benefit.

Citation: Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;151(8):517-527.

Clinical question: Does long-term inhaled corticosteroid therapy, with and without long-acting beta-agonists, decrease airway inflammation and improve lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD)?

Background: Guideline-recommended treatment of COPD with inhaled corticosteroids and long-acting beta-agonists improves symptoms and exacerbation rates; little is known about the impact of these therapies on inflammation and long-term lung function.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Two university medical centers in the Netherlands.

Synopsis: One hundred one steroid-naïve patients, ages 45 to 75 who were current or former smokers with moderate to severe COPD, were randomized to one of four regimens: 1) fluticasone for six months, then placebo for 24 months; 2) fluticasone for 30 months; 3) fluticasone and salmeterol for 30 months; or 4) placebo for 30 months. The primary outcome was inflammatory cell counts in bronchial biopsies/induced sputum. Secondary outcomes included postbronchodilator spirometry, methacholine hyperresponsiveness, and self-reported symptoms and health status. Patients with asthma were excluded.

Short-term fluticasone therapy decreased inflammation and improved forced expiratory volume in one second (FEV1). Long-term therapy also decreased the rate of FEV1 decline, reduced dyspnea, and improved health status. Discontinuation of therapy at six months led to inflammation relapse with worsened symptoms and increased rate of FEV1 decline. The addition of long-acting beta-agonists did not provide additional anti-inflammatory benefits, but it did improve FEV1 and dyspnea at six months.

Additional studies are needed to further define clinical outcomes and assess the cost benefit of these therapies.

Bottom line: Inhaled corticosteroids decrease inflammation in steroid-naïve patients with moderate to severe COPD and might decrease the rate of lung function decline. Long-acting beta-agonists do not offer additional anti-inflammatory benefit.

Citation: Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;151(8):517-527.

Clinical question: Do resident fatigue and distress contribute to medical errors?

Background: In recent years, such measures as work-hour limitations have been implemented to decrease resident fatigue and, it is presumed, medical errors. However, few studies address the relationship between residents’ well-being and self-reported medical errors.

Study design: Prospective six-year longitudinal cohort study.

Setting: Single academic medical center.

Synopsis: The authors had 380 internal-medicine residents complete quarterly surveys to assess fatigue, quality of life, burnout, symptoms of depression, and frequency of perceived medical errors. In a univariate analysis, fatigue/sleepiness, burnout, depression, and overall quality of life measures correlated significantly with self-reported major medical errors. Fatigue/sleepiness and measures of distress additively increased the risk of self-reported errors. Increases in one or both domains were estimated to increase the risk of self-reported errors by as much as 15% to 28%.

The authors studied only self-reported medical errors. It is difficult to know whether these errors directly affected patient outcomes. Additionally, results of this single-site study might not be able to be generalized.

Bottom line: Fatigue and distress contribute to self-perceived medical errors among residents.

Citation: West CP, Tan AD, Habermann TM, Sloan JA, Shanafelt TD. Association of resident fatigue and distress with perceived medical errors. JAMA. 2009;302(12):1294-1300.

Clinical question: Do resident fatigue and distress contribute to medical errors?

Background: In recent years, such measures as work-hour limitations have been implemented to decrease resident fatigue and, it is presumed, medical errors. However, few studies address the relationship between residents’ well-being and self-reported medical errors.

Study design: Prospective six-year longitudinal cohort study.

Setting: Single academic medical center.

Synopsis: The authors had 380 internal-medicine residents complete quarterly surveys to assess fatigue, quality of life, burnout, symptoms of depression, and frequency of perceived medical errors. In a univariate analysis, fatigue/sleepiness, burnout, depression, and overall quality of life measures correlated significantly with self-reported major medical errors. Fatigue/sleepiness and measures of distress additively increased the risk of self-reported errors. Increases in one or both domains were estimated to increase the risk of self-reported errors by as much as 15% to 28%.

The authors studied only self-reported medical errors. It is difficult to know whether these errors directly affected patient outcomes. Additionally, results of this single-site study might not be able to be generalized.

Bottom line: Fatigue and distress contribute to self-perceived medical errors among residents.

Citation: West CP, Tan AD, Habermann TM, Sloan JA, Shanafelt TD. Association of resident fatigue and distress with perceived medical errors. JAMA. 2009;302(12):1294-1300.

Clinical question: Do resident fatigue and distress contribute to medical errors?

Background: In recent years, such measures as work-hour limitations have been implemented to decrease resident fatigue and, it is presumed, medical errors. However, few studies address the relationship between residents’ well-being and self-reported medical errors.

Study design: Prospective six-year longitudinal cohort study.

Setting: Single academic medical center.

Synopsis: The authors had 380 internal-medicine residents complete quarterly surveys to assess fatigue, quality of life, burnout, symptoms of depression, and frequency of perceived medical errors. In a univariate analysis, fatigue/sleepiness, burnout, depression, and overall quality of life measures correlated significantly with self-reported major medical errors. Fatigue/sleepiness and measures of distress additively increased the risk of self-reported errors. Increases in one or both domains were estimated to increase the risk of self-reported errors by as much as 15% to 28%.

The authors studied only self-reported medical errors. It is difficult to know whether these errors directly affected patient outcomes. Additionally, results of this single-site study might not be able to be generalized.

Bottom line: Fatigue and distress contribute to self-perceived medical errors among residents.

Citation: West CP, Tan AD, Habermann TM, Sloan JA, Shanafelt TD. Association of resident fatigue and distress with perceived medical errors. JAMA. 2009;302(12):1294-1300.

Clinical question: Is dabigatran, an oral thrombin inhibitor, an effective and safe alternative to warfarin in patients with atrial fibrillation?

Background: Warfarin reduces the risk of stroke among patients with atrial fibrillation (AF) but requires frequent laboratory monitoring. Dabigatran is an oral direct thrombin inhibitor given in fixed dosages without laboratory monitoring.

Study design: Randomized, multicenter, open-label, noninferiority trial.

Setting: 951 clinical centers in 44 countries.

Synopsis: More than 18,000 patients 65 and older with AF and at least one stroke risk factor were enrolled. The average CHADS2 score was 2.1. Patients were randomized to receive fixed doses of dabigatran (110 mg or 150 mg, twice daily) or warfarin adjusted to an INR of 2.0-3.0. The primary outcomes were a) stroke or systemic embolism and b) major hemorrhage. Median followup was two years.

The annual rates of stroke or systemic embolism for both doses of dabigatran were noninferior to warfarin (P<0.001); higher-dose dabigatran was statistically superior to warfarin (relative risk (RR)=0.66, P<0.001). The annual rate of major hemorrhage was lowest in the lower-dose dabigatran group (RR=0.80, P=0.003 compared with warfarin); the higher-dose dabigatran and warfarin groups had equivalent rates of major bleeding. No increased risk of liver function abnormalities was noted.

Bottom line: Dabigatran appears to be an effective and safe alternative to warfarin in AF patients. If the drug were to be FDA-approved, appropriate patient selection and cost will need to be established.

Citation: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.

Clinical question: Is dabigatran, an oral thrombin inhibitor, an effective and safe alternative to warfarin in patients with atrial fibrillation?

Background: Warfarin reduces the risk of stroke among patients with atrial fibrillation (AF) but requires frequent laboratory monitoring. Dabigatran is an oral direct thrombin inhibitor given in fixed dosages without laboratory monitoring.

Study design: Randomized, multicenter, open-label, noninferiority trial.

Setting: 951 clinical centers in 44 countries.

Synopsis: More than 18,000 patients 65 and older with AF and at least one stroke risk factor were enrolled. The average CHADS2 score was 2.1. Patients were randomized to receive fixed doses of dabigatran (110 mg or 150 mg, twice daily) or warfarin adjusted to an INR of 2.0-3.0. The primary outcomes were a) stroke or systemic embolism and b) major hemorrhage. Median followup was two years.

The annual rates of stroke or systemic embolism for both doses of dabigatran were noninferior to warfarin (P<0.001); higher-dose dabigatran was statistically superior to warfarin (relative risk (RR)=0.66, P<0.001). The annual rate of major hemorrhage was lowest in the lower-dose dabigatran group (RR=0.80, P=0.003 compared with warfarin); the higher-dose dabigatran and warfarin groups had equivalent rates of major bleeding. No increased risk of liver function abnormalities was noted.

Bottom line: Dabigatran appears to be an effective and safe alternative to warfarin in AF patients. If the drug were to be FDA-approved, appropriate patient selection and cost will need to be established.

Citation: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.

Clinical question: Is dabigatran, an oral thrombin inhibitor, an effective and safe alternative to warfarin in patients with atrial fibrillation?

Background: Warfarin reduces the risk of stroke among patients with atrial fibrillation (AF) but requires frequent laboratory monitoring. Dabigatran is an oral direct thrombin inhibitor given in fixed dosages without laboratory monitoring.

Study design: Randomized, multicenter, open-label, noninferiority trial.

Setting: 951 clinical centers in 44 countries.

Synopsis: More than 18,000 patients 65 and older with AF and at least one stroke risk factor were enrolled. The average CHADS2 score was 2.1. Patients were randomized to receive fixed doses of dabigatran (110 mg or 150 mg, twice daily) or warfarin adjusted to an INR of 2.0-3.0. The primary outcomes were a) stroke or systemic embolism and b) major hemorrhage. Median followup was two years.

The annual rates of stroke or systemic embolism for both doses of dabigatran were noninferior to warfarin (P<0.001); higher-dose dabigatran was statistically superior to warfarin (relative risk (RR)=0.66, P<0.001). The annual rate of major hemorrhage was lowest in the lower-dose dabigatran group (RR=0.80, P=0.003 compared with warfarin); the higher-dose dabigatran and warfarin groups had equivalent rates of major bleeding. No increased risk of liver function abnormalities was noted.

Bottom line: Dabigatran appears to be an effective and safe alternative to warfarin in AF patients. If the drug were to be FDA-approved, appropriate patient selection and cost will need to be established.

Citation: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.

Clinical question: Does cardiac resynchronization therapy (CRT) with biventricular pacing decrease cardiac events in patients with reduced ejection fraction (EF) and wide QRS complex but only mild cardiac symptoms?

Background: In patients with severely reduced EF, implantable cardioverter defibrillators (ICDs) have been shown to improve survival. Meanwhile, CRT decreases heart-failure-related hospitalizations for patients with advanced heart-failure symptoms, EF less than 35%, and intraventricular conduction delay. It is not as clear whether patients with less-severe symptoms benefit from CRT.

Study design: Randomized, controlled trial.

Setting: 110 medical centers in the U.S., Canada, and Europe.

Synopsis: This Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study randomly assigned 1,820 adults with EF less than 30%, New York Health Association Class I or II congestive heart failure, and in sinus rhythm with QRS greater than 130 msec to receive ICD with CRT or ICD alone. The primary endpoint was all-cause mortality or nonfatal heart-failure events. Average followup was 2.4 years.

A 34% reduction in the primary endpoint was found in the ICD-CRT group when compared with the ICD-only group, primarily due to a 41% reduction in heart-failure events. In a subgroup analysis, women and patients with QRS greater than 150 msec experienced particular benefit. Echocardiography one year after device implantation demonstrated significant reductions in left ventricular end-systolic and end-diastolic volume, and a significant increase in EF with ICD-CRT versus ICD-only (P<0.001).

Bottom line: Compared with ICD alone, CRT in combination with ICD prevented heart-failure events in relatively asymptomatic heart-failure patients with low EF and prolonged QRS.

Citation: Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329-1338.

Clinical question: Does cardiac resynchronization therapy (CRT) with biventricular pacing decrease cardiac events in patients with reduced ejection fraction (EF) and wide QRS complex but only mild cardiac symptoms?

Background: In patients with severely reduced EF, implantable cardioverter defibrillators (ICDs) have been shown to improve survival. Meanwhile, CRT decreases heart-failure-related hospitalizations for patients with advanced heart-failure symptoms, EF less than 35%, and intraventricular conduction delay. It is not as clear whether patients with less-severe symptoms benefit from CRT.

Study design: Randomized, controlled trial.

Setting: 110 medical centers in the U.S., Canada, and Europe.

Synopsis: This Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study randomly assigned 1,820 adults with EF less than 30%, New York Health Association Class I or II congestive heart failure, and in sinus rhythm with QRS greater than 130 msec to receive ICD with CRT or ICD alone. The primary endpoint was all-cause mortality or nonfatal heart-failure events. Average followup was 2.4 years.

A 34% reduction in the primary endpoint was found in the ICD-CRT group when compared with the ICD-only group, primarily due to a 41% reduction in heart-failure events. In a subgroup analysis, women and patients with QRS greater than 150 msec experienced particular benefit. Echocardiography one year after device implantation demonstrated significant reductions in left ventricular end-systolic and end-diastolic volume, and a significant increase in EF with ICD-CRT versus ICD-only (P<0.001).

Bottom line: Compared with ICD alone, CRT in combination with ICD prevented heart-failure events in relatively asymptomatic heart-failure patients with low EF and prolonged QRS.

Citation: Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329-1338.

Clinical question: Does cardiac resynchronization therapy (CRT) with biventricular pacing decrease cardiac events in patients with reduced ejection fraction (EF) and wide QRS complex but only mild cardiac symptoms?

Background: In patients with severely reduced EF, implantable cardioverter defibrillators (ICDs) have been shown to improve survival. Meanwhile, CRT decreases heart-failure-related hospitalizations for patients with advanced heart-failure symptoms, EF less than 35%, and intraventricular conduction delay. It is not as clear whether patients with less-severe symptoms benefit from CRT.

Study design: Randomized, controlled trial.

Setting: 110 medical centers in the U.S., Canada, and Europe.

Synopsis: This Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study randomly assigned 1,820 adults with EF less than 30%, New York Health Association Class I or II congestive heart failure, and in sinus rhythm with QRS greater than 130 msec to receive ICD with CRT or ICD alone. The primary endpoint was all-cause mortality or nonfatal heart-failure events. Average followup was 2.4 years.

A 34% reduction in the primary endpoint was found in the ICD-CRT group when compared with the ICD-only group, primarily due to a 41% reduction in heart-failure events. In a subgroup analysis, women and patients with QRS greater than 150 msec experienced particular benefit. Echocardiography one year after device implantation demonstrated significant reductions in left ventricular end-systolic and end-diastolic volume, and a significant increase in EF with ICD-CRT versus ICD-only (P<0.001).

Bottom line: Compared with ICD alone, CRT in combination with ICD prevented heart-failure events in relatively asymptomatic heart-failure patients with low EF and prolonged QRS.

Citation: Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329-1338.

Clinical question: Does perioperative fluvastatin decrease adverse cardiac events after vascular surgery?

Background: Patients with atherosclerotic vascular disease who undergo vascular surgery are at high risk for postoperative cardiac events. Studies in nonsurgical populations have shown the beneficial effects of statin therapy on cardiac outcomes. However, no placebo-controlled trials have addressed the effect of statins on postoperative cardiac outcomes.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Single large academic medical center in the Netherlands.

Synopsis: The study looked at 497 statin-naïve patients 40 years or older undergoing non-cardiac vascular surgery. The patients were randomized to 80 mg of extended-release fluvastatin versus placebo; all patients received a beta-blocker. Therapy began preoperatively (median of 37 days) and continued for at least 30 days after surgery. Outcomes were assessed at 30 days post-surgery.

Postoperative myocardial infarction (MI) was significantly less common in the fluvastatin group than with placebo (10.8% vs. 19%, hazard ratio (HR) 0.55, P=0.01). In addition, the treatment group had a lower frequency of death from cardiovascular causes (4.8% vs. 10.1%, HR 0.47, P=0.03). Statin therapy was not associated with an increased rate of adverse events.

Notably, all of the patients enrolled in this study were high-risk patients undergoing high-risk (vascular) surgery. Patients already on statins were excluded.

Further studies are needed to determine whether the findings can be extrapolated to other populations, including nonvascular surgery patients.

Bottom line: Perioperative statin therapy resulted in a significant decrease in postoperative MI and death within 30 days of vascular surgery.

Citation: Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361(10):980-989.

Clinical question: Does perioperative fluvastatin decrease adverse cardiac events after vascular surgery?

Background: Patients with atherosclerotic vascular disease who undergo vascular surgery are at high risk for postoperative cardiac events. Studies in nonsurgical populations have shown the beneficial effects of statin therapy on cardiac outcomes. However, no placebo-controlled trials have addressed the effect of statins on postoperative cardiac outcomes.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Single large academic medical center in the Netherlands.

Synopsis: The study looked at 497 statin-naïve patients 40 years or older undergoing non-cardiac vascular surgery. The patients were randomized to 80 mg of extended-release fluvastatin versus placebo; all patients received a beta-blocker. Therapy began preoperatively (median of 37 days) and continued for at least 30 days after surgery. Outcomes were assessed at 30 days post-surgery.

Postoperative myocardial infarction (MI) was significantly less common in the fluvastatin group than with placebo (10.8% vs. 19%, hazard ratio (HR) 0.55, P=0.01). In addition, the treatment group had a lower frequency of death from cardiovascular causes (4.8% vs. 10.1%, HR 0.47, P=0.03). Statin therapy was not associated with an increased rate of adverse events.

Notably, all of the patients enrolled in this study were high-risk patients undergoing high-risk (vascular) surgery. Patients already on statins were excluded.

Further studies are needed to determine whether the findings can be extrapolated to other populations, including nonvascular surgery patients.

Bottom line: Perioperative statin therapy resulted in a significant decrease in postoperative MI and death within 30 days of vascular surgery.

Citation: Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361(10):980-989.

Clinical question: Does perioperative fluvastatin decrease adverse cardiac events after vascular surgery?

Background: Patients with atherosclerotic vascular disease who undergo vascular surgery are at high risk for postoperative cardiac events. Studies in nonsurgical populations have shown the beneficial effects of statin therapy on cardiac outcomes. However, no placebo-controlled trials have addressed the effect of statins on postoperative cardiac outcomes.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Single large academic medical center in the Netherlands.

Synopsis: The study looked at 497 statin-naïve patients 40 years or older undergoing non-cardiac vascular surgery. The patients were randomized to 80 mg of extended-release fluvastatin versus placebo; all patients received a beta-blocker. Therapy began preoperatively (median of 37 days) and continued for at least 30 days after surgery. Outcomes were assessed at 30 days post-surgery.

Postoperative myocardial infarction (MI) was significantly less common in the fluvastatin group than with placebo (10.8% vs. 19%, hazard ratio (HR) 0.55, P=0.01). In addition, the treatment group had a lower frequency of death from cardiovascular causes (4.8% vs. 10.1%, HR 0.47, P=0.03). Statin therapy was not associated with an increased rate of adverse events.

Notably, all of the patients enrolled in this study were high-risk patients undergoing high-risk (vascular) surgery. Patients already on statins were excluded.

Further studies are needed to determine whether the findings can be extrapolated to other populations, including nonvascular surgery patients.

Bottom line: Perioperative statin therapy resulted in a significant decrease in postoperative MI and death within 30 days of vascular surgery.

Citation: Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361(10):980-989.

Bone marrow biopsy

Credit: Chad McNeeley

The International Myeloma Working Group (IMWG) has published new criteria for diagnosing multiple myeloma (MM) in The Lancet Oncology.

The group has added validated biomarkers to the current clinical symptoms used for MM diagnosis—hypercalcemia, renal failure, anemia, and bone lesions.

This addition will allow physicians to diagnose MM before patients become symptomatic and, therefore, before organ damage occurs, according to the IMWG.

Lead author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota, noted that MM is always preceded sequentially by two conditions—monoclonal gammopathy of undetermined significance and smoldering MM. Since both are asymptomatic, most MM patients are not diagnosed until organ damage occurs.

“The new IMWG criteria allow for the diagnosis of myeloma to be made in patients without symptoms and before organ damage occurs, using validated biomarkers that identify patients with [smoldering] MM who have an ‘ultra-high’ risk of progression to multiple myeloma,” Dr Rajkumar said.

“These biomarkers are associated with the near-inevitable development of clinical symptoms and are important for early diagnosis and treatment, which is very important for patients.”

Other updates to the criteria used to diagnose MM include the use of CT and PET-CT scans to identify bone lesions. According to the authors, this will enable more accurate diagnosis and intervention before fractures or other serious problems arise.

“We believe that the new criteria will rectify the situation where we were unable to use the considerable advances in multiple myeloma therapy prior to organ damage,” Dr Rajkumar said. “We can now initiate therapy in some patients early on in the course of their disease.”

The IMWG’s revised diagnostic criteria for MM and smoldering MM are as follows.

Definition of MM

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and one or more of the following myeloma defining events:

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

  • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL).
  • Renal insufficiency: creatinine clearance <40 mL per min (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL).
  • Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value <100 g/L.
  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If the bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.

• One or more of the following biomarkers:

  • Clonal bone marrow plasma cell percentage ≥60%.
  • Involved:uninvolved serum free light chain ratio ≥100. These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L.
  • >1 focal lesions on MRI studies. Each focal lesion must be 5 mm or more in size.

*The IMWG said clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone

marrow plasma cell percentage should preferably be estimated from a core biopsy specimen. In case of a disparity between the aspirate and core biopsy, the highest value should be used.

Definition of smoldering MM

Both of the following criteria must be met:

• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10%–60%.
• Absence of myeloma defining events or amyloidosis.
  

Bone marrow biopsy

Credit: Chad McNeeley

The International Myeloma Working Group (IMWG) has published new criteria for diagnosing multiple myeloma (MM) in The Lancet Oncology.

The group has added validated biomarkers to the current clinical symptoms used for MM diagnosis—hypercalcemia, renal failure, anemia, and bone lesions.

This addition will allow physicians to diagnose MM before patients become symptomatic and, therefore, before organ damage occurs, according to the IMWG.

Lead author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota, noted that MM is always preceded sequentially by two conditions—monoclonal gammopathy of undetermined significance and smoldering MM. Since both are asymptomatic, most MM patients are not diagnosed until organ damage occurs.

“The new IMWG criteria allow for the diagnosis of myeloma to be made in patients without symptoms and before organ damage occurs, using validated biomarkers that identify patients with [smoldering] MM who have an ‘ultra-high’ risk of progression to multiple myeloma,” Dr Rajkumar said.

“These biomarkers are associated with the near-inevitable development of clinical symptoms and are important for early diagnosis and treatment, which is very important for patients.”

Other updates to the criteria used to diagnose MM include the use of CT and PET-CT scans to identify bone lesions. According to the authors, this will enable more accurate diagnosis and intervention before fractures or other serious problems arise.

“We believe that the new criteria will rectify the situation where we were unable to use the considerable advances in multiple myeloma therapy prior to organ damage,” Dr Rajkumar said. “We can now initiate therapy in some patients early on in the course of their disease.”

The IMWG’s revised diagnostic criteria for MM and smoldering MM are as follows.

Definition of MM

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and one or more of the following myeloma defining events:

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

  • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL).
  • Renal insufficiency: creatinine clearance <40 mL per min (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL).
  • Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value <100 g/L.
  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If the bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.

• One or more of the following biomarkers:

  • Clonal bone marrow plasma cell percentage ≥60%.
  • Involved:uninvolved serum free light chain ratio ≥100. These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L.
  • >1 focal lesions on MRI studies. Each focal lesion must be 5 mm or more in size.

*The IMWG said clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone

marrow plasma cell percentage should preferably be estimated from a core biopsy specimen. In case of a disparity between the aspirate and core biopsy, the highest value should be used.

Definition of smoldering MM

Both of the following criteria must be met:

• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10%–60%.
• Absence of myeloma defining events or amyloidosis.
  

Bone marrow biopsy

Credit: Chad McNeeley

The International Myeloma Working Group (IMWG) has published new criteria for diagnosing multiple myeloma (MM) in The Lancet Oncology.

The group has added validated biomarkers to the current clinical symptoms used for MM diagnosis—hypercalcemia, renal failure, anemia, and bone lesions.

This addition will allow physicians to diagnose MM before patients become symptomatic and, therefore, before organ damage occurs, according to the IMWG.

Lead author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota, noted that MM is always preceded sequentially by two conditions—monoclonal gammopathy of undetermined significance and smoldering MM. Since both are asymptomatic, most MM patients are not diagnosed until organ damage occurs.

“The new IMWG criteria allow for the diagnosis of myeloma to be made in patients without symptoms and before organ damage occurs, using validated biomarkers that identify patients with [smoldering] MM who have an ‘ultra-high’ risk of progression to multiple myeloma,” Dr Rajkumar said.

“These biomarkers are associated with the near-inevitable development of clinical symptoms and are important for early diagnosis and treatment, which is very important for patients.”

Other updates to the criteria used to diagnose MM include the use of CT and PET-CT scans to identify bone lesions. According to the authors, this will enable more accurate diagnosis and intervention before fractures or other serious problems arise.

“We believe that the new criteria will rectify the situation where we were unable to use the considerable advances in multiple myeloma therapy prior to organ damage,” Dr Rajkumar said. “We can now initiate therapy in some patients early on in the course of their disease.”

The IMWG’s revised diagnostic criteria for MM and smoldering MM are as follows.

Definition of MM

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and one or more of the following myeloma defining events:

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

  • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL).
  • Renal insufficiency: creatinine clearance <40 mL per min (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL).
  • Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value <100 g/L.
  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If the bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.

• One or more of the following biomarkers:

  • Clonal bone marrow plasma cell percentage ≥60%.
  • Involved:uninvolved serum free light chain ratio ≥100. These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L.
  • >1 focal lesions on MRI studies. Each focal lesion must be 5 mm or more in size.

*The IMWG said clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone

marrow plasma cell percentage should preferably be estimated from a core biopsy specimen. In case of a disparity between the aspirate and core biopsy, the highest value should be used.

Definition of smoldering MM

Both of the following criteria must be met:

• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10%–60%.
• Absence of myeloma defining events or amyloidosis.
  

Blood sample collection

Credit: Juan D. Alfonso

A new device can measure methotrexate levels in a patient’s blood in less than a minute, according to research published in Biosensors and Bioelectronics.

Researchers say this nanoscale device is just as accurate and 10 times less expensive than equipment currently used in hospitals.

It has an optical system that can rapidly gauge the optimal dose of methotrexate a patient needs, thereby reducing the risk of adverse effects.

“While effective, methotrexate is also highly toxic and can damage the healthy cells of patients, hence the importance of closely monitoring the drug’s concentration in the serum of treated individuals to adjust the dosage,” said study author Jean François Masson, PhD, of the University of Montreal in Quebec, Canada.

“The operation of the current [methotrexate monitoring] device is based on a cumbersome, expensive platform that requires experienced personnel because of the many samples that need to be manipulated.”

With this in mind, Dr Masson and his colleagues set out to simplify methotrexate monitoring.

In the course of their research, the team developed and manufactured a miniaturized device that works by surface plasmon resonance. It measures the concentration of serum methotrexate through gold nanoparticles on the surface of a receptacle.

In “competing” with methotrexate to block the enzyme dihydrofolate reductase, the gold nanoparticles change the color of the light detected by the instrument. And the color of the light detected reflects the exact concentration of the drug in the blood sample.

The researchers compared the accuracy of measurements taken with the new device to those taken with equipment used at the Maisonneuve-Rosemont Hospital in Montreal.

“Testing was conclusive,” Dr Masson said. “Not only were the measurements as accurate, but our device took less than 60 seconds to produce results, compared to 30 minutes for current devices.”

Moreover, the comparative tests were performed by lab technicians who were not experienced with surface plasmon resonance and did not encounter major difficulties in operating the new equipment or obtaining the same conclusive results as Dr Masson and his research team.

“In the near future, we can foresee the device in doctors’ offices or even at the bedside, where patients would receive individualized and optimal doses while minimizing the risk of complications,” Dr Masson said.

“While traditional equipment requires an investment of around $100,000, the new mobile device would likely cost 10 times less, around $10,000.”

Blood sample collection

Credit: Juan D. Alfonso

A new device can measure methotrexate levels in a patient’s blood in less than a minute, according to research published in Biosensors and Bioelectronics.

Researchers say this nanoscale device is just as accurate and 10 times less expensive than equipment currently used in hospitals.

It has an optical system that can rapidly gauge the optimal dose of methotrexate a patient needs, thereby reducing the risk of adverse effects.

“While effective, methotrexate is also highly toxic and can damage the healthy cells of patients, hence the importance of closely monitoring the drug’s concentration in the serum of treated individuals to adjust the dosage,” said study author Jean François Masson, PhD, of the University of Montreal in Quebec, Canada.

“The operation of the current [methotrexate monitoring] device is based on a cumbersome, expensive platform that requires experienced personnel because of the many samples that need to be manipulated.”

With this in mind, Dr Masson and his colleagues set out to simplify methotrexate monitoring.

In the course of their research, the team developed and manufactured a miniaturized device that works by surface plasmon resonance. It measures the concentration of serum methotrexate through gold nanoparticles on the surface of a receptacle.

In “competing” with methotrexate to block the enzyme dihydrofolate reductase, the gold nanoparticles change the color of the light detected by the instrument. And the color of the light detected reflects the exact concentration of the drug in the blood sample.

The researchers compared the accuracy of measurements taken with the new device to those taken with equipment used at the Maisonneuve-Rosemont Hospital in Montreal.

“Testing was conclusive,” Dr Masson said. “Not only were the measurements as accurate, but our device took less than 60 seconds to produce results, compared to 30 minutes for current devices.”

Moreover, the comparative tests were performed by lab technicians who were not experienced with surface plasmon resonance and did not encounter major difficulties in operating the new equipment or obtaining the same conclusive results as Dr Masson and his research team.

“In the near future, we can foresee the device in doctors’ offices or even at the bedside, where patients would receive individualized and optimal doses while minimizing the risk of complications,” Dr Masson said.

“While traditional equipment requires an investment of around $100,000, the new mobile device would likely cost 10 times less, around $10,000.”

Blood sample collection

Credit: Juan D. Alfonso

A new device can measure methotrexate levels in a patient’s blood in less than a minute, according to research published in Biosensors and Bioelectronics.

Researchers say this nanoscale device is just as accurate and 10 times less expensive than equipment currently used in hospitals.

It has an optical system that can rapidly gauge the optimal dose of methotrexate a patient needs, thereby reducing the risk of adverse effects.

“While effective, methotrexate is also highly toxic and can damage the healthy cells of patients, hence the importance of closely monitoring the drug’s concentration in the serum of treated individuals to adjust the dosage,” said study author Jean François Masson, PhD, of the University of Montreal in Quebec, Canada.

“The operation of the current [methotrexate monitoring] device is based on a cumbersome, expensive platform that requires experienced personnel because of the many samples that need to be manipulated.”

With this in mind, Dr Masson and his colleagues set out to simplify methotrexate monitoring.

In the course of their research, the team developed and manufactured a miniaturized device that works by surface plasmon resonance. It measures the concentration of serum methotrexate through gold nanoparticles on the surface of a receptacle.

In “competing” with methotrexate to block the enzyme dihydrofolate reductase, the gold nanoparticles change the color of the light detected by the instrument. And the color of the light detected reflects the exact concentration of the drug in the blood sample.

The researchers compared the accuracy of measurements taken with the new device to those taken with equipment used at the Maisonneuve-Rosemont Hospital in Montreal.

“Testing was conclusive,” Dr Masson said. “Not only were the measurements as accurate, but our device took less than 60 seconds to produce results, compared to 30 minutes for current devices.”

Moreover, the comparative tests were performed by lab technicians who were not experienced with surface plasmon resonance and did not encounter major difficulties in operating the new equipment or obtaining the same conclusive results as Dr Masson and his research team.

“In the near future, we can foresee the device in doctors’ offices or even at the bedside, where patients would receive individualized and optimal doses while minimizing the risk of complications,” Dr Masson said.

“While traditional equipment requires an investment of around $100,000, the new mobile device would likely cost 10 times less, around $10,000.”

Red blood cells

The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal

hemoglobinuria (PNH).

Roughly 2 months ago, the European Medicines Agency (EMA) did the same.

Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is

planning to move the drug into clinical trials in 2015.

If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.

“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.

Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.

About AMY-101 and PNH

PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.

The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.

Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.

In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.

The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.

These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.

The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.

Red blood cells

The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal

hemoglobinuria (PNH).

Roughly 2 months ago, the European Medicines Agency (EMA) did the same.

Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is

planning to move the drug into clinical trials in 2015.

If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.

“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.

Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.

About AMY-101 and PNH

PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.

The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.

Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.

In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.

The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.

These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.

The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.

Red blood cells

The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal

hemoglobinuria (PNH).

Roughly 2 months ago, the European Medicines Agency (EMA) did the same.

Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is

planning to move the drug into clinical trials in 2015.

If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.

“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.

Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.

About AMY-101 and PNH

PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.

The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.

Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.

In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.

The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.

These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.

The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.

Woman texting

Credit: Ed Yourdon

Text messages reminding patients to take malaria medication can improve treatment adherence, according to a study published in PLOS ONE.

“When patients don’t complete their full medication regimen, diseases can develop resistance to treatment,” said study author Julia Raifman, a PhD candidate at the Harvard School of Public Health in Boston.

“And with infectious diseases like malaria, drug-resistant diseases can spread to others. We’ve already begun to see resistance to artemisinin in Southeast Asia. It would be catastrophic if that became widespread and there was no effective treatment for the most deadly form of malaria.”

Working with researchers at the non-profit Innovations for Poverty Action in Ghana, Raifman and her colleagues drew on previous research using SMS reminders in situations where people fail to follow through on intentions, such as saving money, paying back loans, or completing college financial aid forms.

The researchers recruited 1140 people in Ghana who were taking artemisinin-based combination therapy to treat malaria.

Participants used their mobile phones to enroll in an automated system, and the system randomly assigned half of them to receive the text message reminders to take their medication.

Local researchers followed up with the participants several days later at their homes to see how many pills they had taken. Subjects who received the texts were significantly more likely to finish the full regimen.

The researchers also tested whether a short or longer, more informative message would be more effective. They were surprised to find the shorter messages had a significant impact, but the longer ones did not.

“SMS reminders are a ‘nudge,’ not a ‘shove,’” said Aaron Dibner-Dunlap, of Innovations for Poverty Action. “They can help people follow through on something they originally intended to do, but human nature is tricky, and the science is still young.”

“We’re optimistic because the technology has become so widespread and inexpensive to administer, that for programs like this one that work, there’s huge potential for helping people at very low cost.”

Woman texting

Credit: Ed Yourdon

Text messages reminding patients to take malaria medication can improve treatment adherence, according to a study published in PLOS ONE.

“When patients don’t complete their full medication regimen, diseases can develop resistance to treatment,” said study author Julia Raifman, a PhD candidate at the Harvard School of Public Health in Boston.

“And with infectious diseases like malaria, drug-resistant diseases can spread to others. We’ve already begun to see resistance to artemisinin in Southeast Asia. It would be catastrophic if that became widespread and there was no effective treatment for the most deadly form of malaria.”

Working with researchers at the non-profit Innovations for Poverty Action in Ghana, Raifman and her colleagues drew on previous research using SMS reminders in situations where people fail to follow through on intentions, such as saving money, paying back loans, or completing college financial aid forms.

The researchers recruited 1140 people in Ghana who were taking artemisinin-based combination therapy to treat malaria.

Participants used their mobile phones to enroll in an automated system, and the system randomly assigned half of them to receive the text message reminders to take their medication.

Local researchers followed up with the participants several days later at their homes to see how many pills they had taken. Subjects who received the texts were significantly more likely to finish the full regimen.

The researchers also tested whether a short or longer, more informative message would be more effective. They were surprised to find the shorter messages had a significant impact, but the longer ones did not.

“SMS reminders are a ‘nudge,’ not a ‘shove,’” said Aaron Dibner-Dunlap, of Innovations for Poverty Action. “They can help people follow through on something they originally intended to do, but human nature is tricky, and the science is still young.”

“We’re optimistic because the technology has become so widespread and inexpensive to administer, that for programs like this one that work, there’s huge potential for helping people at very low cost.”

Woman texting

Credit: Ed Yourdon

Text messages reminding patients to take malaria medication can improve treatment adherence, according to a study published in PLOS ONE.

“When patients don’t complete their full medication regimen, diseases can develop resistance to treatment,” said study author Julia Raifman, a PhD candidate at the Harvard School of Public Health in Boston.

“And with infectious diseases like malaria, drug-resistant diseases can spread to others. We’ve already begun to see resistance to artemisinin in Southeast Asia. It would be catastrophic if that became widespread and there was no effective treatment for the most deadly form of malaria.”

Working with researchers at the non-profit Innovations for Poverty Action in Ghana, Raifman and her colleagues drew on previous research using SMS reminders in situations where people fail to follow through on intentions, such as saving money, paying back loans, or completing college financial aid forms.

The researchers recruited 1140 people in Ghana who were taking artemisinin-based combination therapy to treat malaria.

Participants used their mobile phones to enroll in an automated system, and the system randomly assigned half of them to receive the text message reminders to take their medication.

Local researchers followed up with the participants several days later at their homes to see how many pills they had taken. Subjects who received the texts were significantly more likely to finish the full regimen.

The researchers also tested whether a short or longer, more informative message would be more effective. They were surprised to find the shorter messages had a significant impact, but the longer ones did not.

“SMS reminders are a ‘nudge,’ not a ‘shove,’” said Aaron Dibner-Dunlap, of Innovations for Poverty Action. “They can help people follow through on something they originally intended to do, but human nature is tricky, and the science is still young.”

“We’re optimistic because the technology has become so widespread and inexpensive to administer, that for programs like this one that work, there’s huge potential for helping people at very low cost.”